Triiron Complex with N-Ferrocenyl Aminocarbyne Ligand Bridging a Diiron Core: DFT, Electrochemical, and Biological Insights

The first N-ferrocenyl aminocarbyne complex, [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Fc)}]CF3SO3 ([2]CF3SO3), was synthesized with an 88% yield from [Fe2Cp2(CO)4], isocyanoferrocene (CNFc), and methyl triflate. The synthesis proceeded through the intermediate formation of [Fe2Cp2(CO)3(CNFc)], 1. Multinuclear NMR experiments revealed the presence of cis and trans isomers for [2]CF3SO3 in organic solvents, in agreement with DFT outcomes. Electrochemical and spectroelectrochemical studies demonstrated one reduction process occurring prevalently at the diiron core and one oxidation involving the ferrocenyl substituent. The oxidation process is expected to favor the redox activation of [2]+ in a biological environment. Both [2]CF3SO3 and its phenyl analogue [Fe2Cp2(CO)2(μ-CO){μ-CN(Me)(Ph)}]CF3SO3 ([3]CF3SO3), prepared for comparison, exerted moderate antiproliferative activity against the human cancer cell lines A431, HCT-15, PSN-1, 2008, and U1285. However, [2]CF3SO3 exhibited a higher cytotoxicity than [3]CF3SO3, showed a substantial ability to induce intracellular ROS production, and outperformed cisplatin in a three-dimensional SCLC cell model.


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collected using an ethyl acetate/heptane mixture (1:9 v/v).Yield 2.48 g, 78 %. 1 H NMR spectrum was consistent with the literature. 1 Next, deaerated hydrazine monohydrate (15 mL) was added to a suspension of N-ferrocenyl phthalimide (2.48 g, 7.47 mmol) in deaerated ethanol (50 mL) in a Schlenk flask, and the resulting mixture was refluxed for 4 h.The reaction mixture was subsequently cooled to 0 °C, and deaerated water (100 mL) was added.The resulting mixture was extracted with Et2O (4 x 50 mL), and the organic phase was dried over Na2SO4.The solvent was evaporated under vacuum, thus aminoferrocene was obtained as yellow solid.Yield 1.20 g, 80 %.Herein we report an optimized, 15 g-scale synthesis of phenyl formamide based on the procedure of Bhanange and co-workers. 5In a 50 mL round bottom flask, 98 % formic acid (6 mL, ca.156 mmol) was introduced and heated at 60 °C.Aniline (12 mL, 132 mmol) was rapidly added to the hot solution under vigorous stirring.The mixture was kept at 60 °C for 2.5 h then diluted with Et2O (20 mL) and moved into a separatory funnel.The organic solution was extracted with a saturated NaHCO3 solution (30 mL; caution!considerable CO2 evolution inside the funnel) then water (3 x 30 mL).Volatiles were removed under vacuum from the Et2O solution, affording a pale red oil.The residue was dissolved in CH2Cl2 and moved on top of a silica column (h 7 cm, d 5.3 cm).Impurities were eluted with CH2Cl2, then a pale yellow band was eluted with Et2O.The eluate was taken to dryness under vacuum, affording an oil that was cooled to -20 °C for 2-3 h to allow solidification.

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Characterization of ferrocenyl isocyanide    The pure cis isomer was serendipitously isolated by alumina chromatography in a non-reproducible way.

Figure S18 .
Figure S18.IR spectra of a CH2Cl2 solution of [2]CF3SO3 recorded in an OTTLE cell a) during the progressive decrease of the WE potential from -1.3 to -1.8 V (vs FeCp2; scan rate 1 mV sec -1 ); b) during 10 minutes in the cell without an applied potential.Starred peak is due to impurities.[N n Bu4]PF6 (0.2 mol dm −3 ) as the supporting electrolyte.The absorptions of the solvent and supporting electrolyte have been subtracted.

Figure S19 .
Figure S19.Profile of the current vs time during the bulk electrolysis of a CH2Cl2 solution of [2]CF3SO3 at a Pt electrode.The total charge Q at t = 560 sec corresponds to 1 electron per molecule.

Figure S20 .S18Figure S21 .
Figure S20.IR spectra of a THF solution of [3]CF3SO3 recorded in an OTTLE cell during the progressive decrease of the WE potential from -1.2 to -1.6 V (vs FeCp2; scan rate 1 mV sec -1 ).Starred peak is due to impurities.[N n Bu4]PF6 (0.2 mol dm −3 ) as the supporting electrolyte.The absorptions of the solvent and supporting electrolyte have been subtracted.